In the treatment of hypertension to reduce the risks of complications such as coronary heart diseases and cardiovascular diseases, e.g., stroke, heart failure, and myocardial infarction, it is more important to maintain the blood pressure within a normal range on a consistent basis than to simply lower the blood pressure level itself. Accordingly, antihypertensive agents are required to be effective for long-term treatment of hypertension. Further, advanced therapy using a combination of two or more drugs having different pharmacological actions makes it possible to improve preventive or therapeutic effects, while lowering side effects arising from the long term administration of a single drug.
Notable antihypertensive drugs include diuretics, sympatholytic agents, and vasodilators. Vasodilators are most widely prescribed antihypertensive drugs, and they are divided into several groups according to their pharmacological actions which include ACE (angiotensin converting enzyme) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers.
Amlodipine is the generic name for 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridine dicarboxylate. Amlodipine besylate is currently marketed as Novasc (trade mark). Amlodipine is a long-acting calcium channel blocker which is useful in treating cardiovascular disorders such as agina, hypertension, and congestive heart failure.
Losartan is the generic name for 2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazol-5-methanol, which has been disclosed in U.S. Pat. Nos. 5,608,075; 5,138,069; and 5,153,197. Losartan potassium is commercially available as Cozaar (trade mark). Losartan blocks the interaction of angiotensin II and its receptor, and is mainly used for treating hypertension, heart failure, ischemic peripheral circulatory disorder, myocardial ischemia (angina pectoris), diabetic neuropathy, and glaucoma, and also for preventing the progression of post-myocardial infarction heart failure.
The present inventors have found that a combined formulation which comprises amlodipine and losartan having different pharmacological activities is useful for treating hypertension, and have conducted intensive studies on such a combined formulation.
However, when the combined formulation of amlodipine and losartan is prepared by simply mixing the two drugs, undesirable gelation of losartan occurs: Losartan readily dissolves in purified water and is easily released at a relatively high pH (e.g., pH 6.8), but it is very slowly released at a low pH (e.g., pH 2.0 or pH 1.2) because of the gelation. In case Cozaar (trade mark), a commercially available losartan preparation is used, the amount of losartan released over the initial 30 minutes is less than 30% at a pH range of 1.2 to 2.0. In such combined formulation of amlodipine and losartan, amlodipine may also be locked in the losartan gel.
An orally administered preparation generally undergoes disintegration and dissolution in the stomach having a low pH, and therefore, a low dissolution rate at a low pH of an active ingredient in a preparation can result in significant lowering of its bioavailability.
In addition, considering the fact that the pH in the stomach of a normal adult varies widely in a range of 1.0 to 3.5 and Cmax of losartan after food ingestion becomes reduced by about 10%, development on such an amlodipine-losartan combined formulation capable of maintaining a relatively constant dissolution rate at such pH variation in the stomach is needed.